Genetic insight into sick sinus syndrome

• Published in: European Heart Journal
• Main Author: DBDS Genomic Consortium
• Other Authors: Faculty of Medicine, Office of Division of Diagnostic and Support Services, Faculty of Industrial Engineering, Mechanical Engineering and Computer Science, Clinical Laboratory Services, Diagnostics and Blood Bank, Health Sciences, Landspitali - The National University Hospital of Iceland
• Format: Article in Journal/Newspaper
• Language: English
• Published: 2021
• Subjects: Gáttatif; Sykursýki; Sjúkur skiptahnútur; Atrial fibrillation; GWAS; KRT8; Mendelian randomization; Sick sinus syndrome; Genome-Wide Association Study; NAV1.8 Voltage-Gated Sodium Channel; Sick Sinus Syndrome/genetics; Humans; Diabetes Mellitus; Type 2; Atrial Fibrillation/genetics; Pacemaker; Artificial; Cardiology and Cardiovascular Medicine; Iceland
• Online Access: https://hdl.handle.net/20.500.11815/3201; https://doi.org/10.1093/eurheartj/ehaa1108

Funding text This work was partly supported by NordForsk through the funding to PM Heart, project number 90580, the Innovation Fund Denmark (IFD) under File No. 8114-00033B and the Technology Development Fund, Iceland, project number 90580. © The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology. Aims: The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. Methods and results: We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1-1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10-20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). Conclusion: We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF ...